World Health Organization (WHO) statistics show that 122 million planned pregnancies occur worldwide per year. Yet, in spite of the availability of many different female contraceptive methods and condoms, an additional 87 million pregnancies are unintended (representing 42% of all pregnancies), and 46 million pregnancies terminated by abortion. Thus, the development of novel reversible oral male contraceptive agents has been identified as a major advance needed to address this worldwide reproductive health issue by the NIH, Institute of Medicine, and WHO. The purpose of the proposed multi-institutional U54 "Inter- disciplinary Center for Male Contraceptive Research and Drug Development" is to develop new non-hormonal male contraceptive agents. The Prime Objective of the research program of this center, using proven successful interdisciplinary approaches, will be to provide NIH with new and novel contraceptive agents for drug development. This will be accomplished by a highly interactive and collaborative group of research projects by 1) investigating a set of unique protein targets that are critical for spermatogenesis, spermiogenesis, and sperm function, and 2) identifying novel and alternative chemical structures that act via the newly discovered male contraceptive targets of our most promising new contraceptive agents. The specific research projects are: Research Project I: Mechanisms and novel male contraceptive agents that target Hsp90p and elongation factor-la. Joseph S. Tash, Ph.D., PI Research Project II: Cardenolides inhibition of the sperm Na,K-ATPase a4 isoform as contraceptive agent Gustavo Blanco, Ph.D., PI, Research Project III: Small molecule inhibitors of Dmrtl-regulated target genes as male contraceptive agents Leslie Heckert, Ph.D., PI, Research Project IV: Sperm protein tyrosine kinases as targets for small molecule contraceptives William Kinsey, Ph.D., PI The research program includes a New Investigator Development Program that will foster and support new scientists involved in research to develop new male contraceptive agents. The research program is supported by a strong and highly interactive set of Core Units including an Administrative Core, Drug Discovery, Design &Synthesis Core, Drug Development Core, and Imaging Core. The scientists involved in the research projects and cores of this proposed center have a record of success in providing NIH with highly promising reversible non-hormonal male contraceptive agents that are already under drug development in collaboration with NIH. The research program in this center will expand this success into new protein targets involved in regulation of male fertility that will be exploited by cutting edge drug discovery and design approaches for generation of new classes of non-hormonal chemical structures as male contraceptive agents.